The overall goal of this Program is to improve the survival of cancer patients by active specific immunotherapy. To achieve this goal we will utilize melanoma as a model neoplasm. This renewal application represents a continuation of our previous studies with polyvalent melanoma cell vaccine (PMCV) and investigates the in vivo and in vitro mechanisms of PMCV anti-cancer activity. Project 1 will evaluate the role of humoral immune responses to PMCV. Antigens that elicit immune responses to PMCV. Antigens that elicit immune responses in man will be studied following the development of human monoclonal antibodies. The study will determine which antigens are associated with disease regression by active specific immunotherapy. Project II will utilize several established assays to determine their utility as prognostic markers in patients receiving active specific immunotherapy, chemobiotherapy and/or surgery. Patients treated in Project III will receiving active specific immunotherapy, chemobiotherapy and/or surgery. Patients treated in Project III will serve as the study population for specimen procurement and the determination of clinical outcome. Project III has recently completed Phase I and II clinical trials, and has proven that the PMCV is safe and can significantly prolong the disease- free and overall survival of patients with high-risk melanoma in comparison to control patients treated at John Wayne Cancer Institute. In the renewal application, Project III will assess PMCV in Phase III randomized multicenter trial. Additionally, the Project will improve upon current immunological and biological stratification. The execution of these three projects relies on the support of four core components: Clinical Support Services, Biostatistics, Serum, Lymphocyte and Tissue Collection and Analysis, and Quality Services.